Each year in Europe there are about 150,000 new cases of endometrial cancer and about 46,000 women die from the disease (Ferlay et al. (2007) Ann. Onc. 18:581-592). In the United States, about 41,000 new case of endometrial carcinoma are diagnosed per year and 7,300 women die each year (see American Cancer Society statistics available on the internet). The incidence and death rate from endometrial cancer are increasing.
Endometrial cancer (EC) is the most frequent invasive tumors of the female genital tract and the fourth most common in women in western countries (Jemal et al. (2008) CA Cancer J Clin 58:71-96). New methods for the diagnosis, prognosis, and classification of endometrial cancer are needed to combat this deadly disease.
Often endometrial cancer is detected early, in its initial stages, by presentation of disease-related symptoms. Unfortunately, 20% of patients present with myometrial invasion and/or lymph node affectation, which are main indicators related to poor prognosis, decrease in survival rate, and more advanced disease. The primary therapeutic modality for endometrial cancer is surgical treatment.
Common symptoms of uterine cancer (e.g., endometrial cancer) include unusual vaginal bleeding or discharge, trouble urinating, pelvic pain, and pain during intercourse. Uterine cancer usually occurs after menopause. Other risk factors for endometrial cancer include being obese, taking estrogen-alone hormone replacement therapy, treatment with tamixofen and having a genetic predisposition to cancer (e.g., Lynch Syndrome). The standard treatment for endometrial cancer varies depending on the stage of the disease. Treatment usually involves surgery to remove the uterus which is called a hysterectomy, although other options include hormone therapy and radiotherapy.
Methods routinely used in the clinic for diagnosing endometrial cancer include biopsy followed by cytological analysis and/or trans-vaginal ultrasound. The diagnosis of endometrial carcinoma is usually done by pathology examination of an endometrial aspirate (20-30%), and by biopsy-guided hysteroscopy (70-80%). The rate of success of diagnosis with hysteroscopy is over 90%, with false positives in the case of precursor lesions of the endometrial adenocarcinoma (hyperplasias); endometrial polyps, that present a non-negligible degree of malignancy (0-4.8%) and must be removed although asymptomatic or benign appearance; or in the case of diffuse forms of endometrial adenocarcinomas that are difficult to differentiate from an endometrial hyperplasia. Thus, there is a need for a less invasive diagnostic test based on molecular markers. Such a less invasive test based on molecular markers would allow for more routine screening of uterine cancer. A diagnostic test based of molecular markers obtained in a less invasive manner and that has sensitivity and specificity comparable to that of the endometrial biopsy can preclude unnecessary hysteroscopy.
Endometrial carcinomas can be classified into low grade (type I) and high-grade (type 2). Type I endometrioid endometrial cancer (sometimes called estrogen dependent), which represent approximately 80% of new cases, are low grade tumors associated with estrogen stimulation, usually developed in peri- or post-menopausal women and are usually preceded by endometrial hyperplasia with or without atypia. Type II non-endometrioid endometrial cancer usually affects older women, are less differentiated and of worse prognosis, not associated with estrogen stimulation, and are related to atrophic endometrium or, occasionally, with endometrial polyps.
Type I cancers are typically known to have alterations in PTEN, KRAS2, DNA mismatch repair defects, CTNNB1, and have near diploid karyotype. Type II cancers typically have TP53 mutations and ErBB2 overexpression and are mostly non-diploid. Sugiyama et al. ((2003) Clin. Can. Res. 9:5589-5600) reported that certain genes are selectively up or down regulated in type I versus type II endometrial cancers. For example, they found that MLH1 was down-regulated in type I cancers as well as other genes related to DNA damage signaling and repair like O6-methyl-guanine DNA methyltransferase, DNA polymerase α catalytic subunit, and Ku (p70/p80) antigen. VEGF-C was found to be upregulated in type I cancers at the protein and mRNA level as compared to type II cancers. KRAS was found to be upregulated in type II cancers. STAT1 was upregulated in type I cancers and STAT2 was upregulated in type II cancers. Konecny et al. ((2009) British Journal of Cancer 100, 89-95) report that the rate HER2 gene amplification as measured by fluorescence in situ hybridization was greater in type II cancers whereas EGFR expression as measured by IHC techniques was significantly lower in type II cancers. Deng et al. ((2005) Clin. Can. Res. vol. 11, no 23:8258-8264) report that EIG121 is a marker for type I estrogen associated cancers.
Uterine cancers are also classified histologically according to cell-type. The most common cell-type is referred to endometrioid and represents around 80% of the newly diagnosed cases. Other less common uterine cancers are referred to as serous and clear cell carcinomas. Most of the type I cancers are of the endometrioid cell-type whereas the type II cancers are more likely to be non-endometrioid uterine cancers. Type II cancers are more likely to metastasize and have a poorer prognosis than type I cancers. Type I cancers typically have a better prognosis and respond better to therapy.
A number of studies have examined gene-expression profiles for classifying uterine cancers. Sugiyama et al. ((2003) Clin. Canc. Res. 9:5589-5600) report that between the type I and II cancers 45 gene were highly expressed in type I cancers and 24 highly expressed in type I cancers. Risinger et al. ((2003) Canc. Res. 63:6-11) report that microarray analysis of different histologic subtypes of endometrial cancer have distinct gene expression profiles. They found that 191 genes exhibited greater than 2-fold difference in expression between endometrioid and non-endometrioid endometrial cancers.
A number of endometrial cancer biomarkers for endometrial cancer have been identified. Elevated levels of CA 125, CA 15-3, and CA 19-9 are associated with shorter survival time. CA 125 correlates with tumor size and stage and is an independent predictor of the extrauterine spread.
Serum markers for the detection of uterine cancer have been reported in the literature. Yurkovetsky et al. ((2007) Gyn. Onc. 107:58-65) identified that prolactin is a serum biomarker with sensitivity and specificity for endometrial cancer. They found serum CA 125, CA 15-3, and CEA, are higher in patients with Stage III disease as compared to stage I. A five-biomarker panel of prolactin, GH, eotaxin, E-selectin, and TSH discriminated endometrial cancer from ovarian and breast cancer.
Another important issue for clinicians for diagnosis of endometrial cancer relates to synchronous cancers. Guirguis et al. (Gyn. Onc. (2008) 108:370-376) have reported that 10% of ovarian cancer patients have a tumor in the endometrium and 5-25% of patients with endometrial cancer also have a tumor in the ovary. Determining the primary site of a cancer has important treatment implications. Stage III endometrial carcinoma is treated with surgery followed by chemotherapy and/or radiation; while dual primary stage I ovarian and endometrial cancers have a better prognosis and may not require adjuvant therapy.
Current methods of diagnosing endometrial cancer often create discomfort to the patient and sometimes rely on subjective interpretation of visual images. There is a need for less invasive methods of screening for endometrial cancer which are less subjective in interpretation. In addition there is a need for new markers that are useful for the early detection of endometrial cancer. Current methods for detecting endometrial cancer include the dilation and curettage method which is considered the gold standard, but this method is invasive, can cause significant discomfort, and may require a trained pathologist for interpretation, and therefore is not suitable as a general screening tool. Another less invasive method for diagnosing endometrial cancer involves transvaginal ultrasound which measures the thickness of the endometrium. In a study of patients having post-menopausal bleeding, using a cutoff of 4 mm, it was found that transvaginal ultrasound had 100% sensitivity and 60% specificity (Gull et al. (2003) Am. J. Obstet. Gynecol. 188 (2):401-408). In women without vaginal bleeding, the sensitivity of the endometrial thickness measurement was 17% for a threshold 6 mm and 33% for a threshold of 5 mm (Fleischer et al. (2001) Am. J. Obstet. Gynecol. 184:70-75). TVS has a high rate of false positives since other conditions besides endometrial cancer can produce a thicker endometrium. One potential problem with the use of TVS in pre- and peri-menopausal women is that the thickness of the endometrium varies as a function of the phase of the menstrual cycle. Furthermore, women taking tamoxifen also have thicker endometrium. Therefore there is a need for techniques and markers that can complement and/or improve the ability of TVS in the diagnosis of endometrial cancer.
Clearly there is room for improvement in the tools currently available for screening for endometrial cancer.